Samuel Gershon: Events and Memories. 5. THA

The next opening was provided by a series of compounds synthesized by Prof. Adrian Albert at the Australian National University (ANU) in Canberra. He was synthesizing a series of acridine compounds in collaboration with the Chairman of Microbiology as antibacterial agents and possible use against tuberculosis. As the Department of Microbiology, in the next building to ours, was doing elaborate in vitro work, we planned to evaluate the pharmacologic properties of one compound in the series: THA, or 1,2,3,4 - tetrahydro - 5 - aminoacridine.

We started with little pharmacological knowledge of the compound, but had a very good dog model of morphine’s effects. So we studied it as an analeptic. Given IV to a sleeping morphinized dog, THA produced an immediate arousal and return to clear consciousness.

Our interest in this compound expanded when we were contacted by the US Army to discuss our work with anti-hallucinogens. We arranged to have a detailed discussion with them together with colleagues at the University of Melbourne, who had developed different potential compounds. They were interested in our whole program, but particularly THA, because their main hallucinogenic compounds (referred to as incapacitating agents) were related to the pharmacology of Ditran (JB-329), a mixture of two structurally related isomers of an anti-cholinergic drug (Gershon and Olaria 1960). The following day, the colonel in charge turned up with a research grant for us to sign. After we published a number of papers on THA, I received a letter from a psychiatrist at the University of Pittsburgh asking permission to access my FDA submitted IND on THA (Bell and Gershon 1964; Bell, Gershon, Carroll and Holan 1964; Brinkman and Gershon 1983; Gershon 1960; Gershon 1965; Gershon, Naubauer and Sundland 1965; Gershon and Shaw 1958; Neubauer, Sundland and Gershon 1966 a,b). He wished to administer THA to cases of imipramine overdose or poisoning, with or without other sedatives. I granted permission and he published papers on the success of the clinical observations. Apparently he also obtained patents for this use of THA, about which I was not fully informed (Soares and Gershon 1995).

Meanwhile, other investigators tried THA administration in Alzheimer’s patients and also patented their findings. THA was then marketed as a treatment for the condition. Their observations amounted to replication of what we had shown previously; THA clearly produced arousal in many different drug-induced and clinical conditions. THA had a new life for several years as a highly touted treatment for Alzheimer’s and it had a significant effect on the established idea that Alzheimer’s was untreatable. This gave rise to the introduction of other potential therapeutic agents and the field regained some therapeutic hope. My belief is that cholinergic antagonists have considerable therapeutic value and deserve further study. Still, great caution must be adopted because the disease has often been present for many years before treatment is attempted.

I must end this section with my belief that all these antagonists have considerable therapeutic value and deserve further study.